Herpes simplex virus-1 (HSV-1) recurrences can cause many ocular pathologies including, immune cell mediated chronic inflammation in the corneal stroma. If left untreated, the chronic immunoinflammatory reactions in the corneal stroma can give rise to herpetic stromal keratitis (HSK);a disease that results in permanent scarring of the cornea and is a leading cause of infection induced corneal blindness in the United States. The current therapies to manage the HSK lesions have significant downsides. Therefore, investigating novel approaches to control the severity of HSK lesions are urgently needed. In this study, we will explore the role of corneal neuropeptides, substance P (SP) and vasoactive intestinal peptide (VIP), in the progression and severity of HSK lesions in a mouse model. Our long-term goal is to understand the role of neuropeptides in regulating the immunity to HSV-1 infection. Neuropeptides SP and VIP are reported to have differential roles in promoting or inhibiting the inflammation. Our pilot studies demonstrated higher amounts of SP but lower levels of VIP in the mice corneas with severe HSK lesions in comparison to those with mild HSK lesions. Therefore, we hypothesize that neuropeptides SP and VIP in the inflamed cornea regulate the progression and severity of HSK lesions. The development of HSK lesions is immune-mediated, with the involvement of pro-inflammatory cytokines (IL-1, IL-6, IL-2, IFN-3 and TNF-1), chemokines (MIP-1 and MIP-2), and immune cell types such as neutrophils and CD4 T cells. Therefore, we will test our hypothesis by demonstrating that corneal neuropeptides SP and VIP regulate the amounts of pro- and anti-inflammatory cytokines, and chemokines in HSV-1 infected corneas. We will also demonstrate that SP and VIP regulate the influx, survival and effector function of neutrophils and CD4 T cells in virus infected corneas. We anticipate that our findings will provide a novel approach to elucidate the pathogenesis of HSK and may significantly impact the management of this condition. PUBLIC HEALTH RELEVANCE: Recurrent herpes simplex virus type-1 (HSV-1) infection of the cornea results in the development of herpetic stromal keratitis (HSK), a disease that can cause permanent scarring and loss of vision. The current therapies to control HSK have significant drawbacks. In this study, we will investigate a novel approach to manage HSK in a mouse model by understanding the role of corneal neuropeptides in the progression and severity of HSK.